Alzheimer's disease (AD) is a progressive, irreversible brain disorder with no known cause or cure. Symptoms of the disease include memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills. Always fatal, Alzheimer's disease is the most common form of irreversible dementia.
According to the American Health Assistance Foundation (AHAF), more than 4.5 million Americans are believed to have Alzheimer's disease and by 2050, the number could increase to 13.2 million. In every nation where life expectancy has increased, so has the incidence of Alzheimer's disease. Alzheimer's disease is becoming tragically common. It is estimated that there are currently 18 million people worldwide with Alzheimer's disease. This figure is projected to nearly double by 2025 to 34 million people.
Considering the fact that there is at present no effective treatment for this fatal disease, it is an imperative to find new solutions to treat AD.
The sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar affinity for the sigma 1 (σ-1) site, and has micromolar affinity for the sigma (σ-2) site. Haloperidol has similar affinities for both subtypes. Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them. Possible sigma-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. Trends Pharmacol. Sci., 1992, 13:85-86). Most studies have implied that sigma binding sites (receptors) are plasmalemmal elements of the signal transduction cascade. Drugs reported to be selective sigma ligands have been evaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad. Sci., 1996, 93:8072-8077). The existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.
Therefore, compounds binding to the sigma receptor and which are suitable for modulating these receptors are useful in the prevention and/or the treatment of diseases associated with the sigma receptor.
Recently it has been found that the sigma-1 receptor may be involved in the pathologenesis of Alzheimer's disease (Uchida et al., Am J Geriatr Psychiatry 2005; 13:1062-1066).
Thus, it was an objective of the present invention to provide new compounds for the use as active ingredients in medicaments. In particular, these active ingredients should be suitable to modulate the sigma receptor, more particularly the sigma-1 receptor.
Said objective was achieved by providing substituted bicyclic tetrahydropyrrolidine compounds of general formula (I) given below, their stereoisomers, corresponding salts and corresponding solvates thereof.
Thus, one of the aspect of the present invention relates to substituted bicyclic tetrahydropyrrolidine compounds of general formula (I)
wherein                R1 represents a hydrogen atom; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system; an optionally, at least mono-substituted benzhydryl group;        wherein the bond between Y and Z may be unsaturated (Y═Z) or saturated (Y—Z);        in case of Y and Z being (Y═Z), Y represents CH and Z represents C—R6; C—CHR7R7a; a C—(C═O)—R8 group; a C—CH2(SO2)—R9 group; a C—CH2(SO2)—NR10R10a group; or a C—(C═O)—NR10R10a group;        in case of Y and Z being (Y—Z), Y represents CH2; C—R11R12; a CH—(C═O)—R16 group; a CH—(SO2)—R17 group; CH—(SO2)—NR18R18a group; or a CH—(C═O)—NR18R18a group and Z represents CH—R6; CH—CHR7R7a; a CH—(C═O)—R8 group; a CH—CH2(SO2)—R9 group; a CH—CH2(SO2)—NR10R10a group; or a CH—(C═O)—NR10R10a group;        R2, R3, R4, and R6 represent a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system;        R5, R5a, identical or different, represent a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system;        R7, R7a, identical or different, represent a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system;        R8, R9, R13, R14, R15, R16 and R17 represent a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system;        
R10, R10a, identical or different, represent a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system;                R11 and R12, identical or different, represent a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system; a —(SO2)—R13-group; or a R14R15-group;        R18 and R18a, identical or different, represent a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system;        R19 represent a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched alkyl-cycloalkyl group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group is optionally condensed with another, at least mono-substituted mono- or polycyclic ring system;        optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.        
In a preferred aspect of the invention the following proviso applies:                if R19 is methyl,        and Y and Z are (Y═Z)        and Y represent CH,Z may not represent a CH group.        
Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. The term “prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. “Textbook of Drug design and Discovery” Taylor & Francis (April 2002).
Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C or 14C-enriched carbon or 15N-enriched nitrogen are within the scope of this invention.
The term “pharmacological tool” refers to the property of compounds of the invention through which they are particularly selective ligands for Sigma receptors which implies that compound of formula (I), described in this invention, can be used as a model for testing other compounds as sigma ligands, ex. a radioactive ligands being replaced, and can also be used for modeling physiological actions related to sigma receptors.
The term “salt” is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions.
The term “physiologically acceptable salt” means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic-especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention—usually a (deprotonated) acid—as an anion with at least one, preferably inorganic, cation which is physiologically tolerated—especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH4, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
These physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention—usually protonated, for example on the nitrogen—as the cation with at least one anion which are physiologically tolerated—especially if used on humans and/or mammals. By this is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated—especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
The compounds of the invention may be in crystalline form or either as free compounds or as solvates and it is intended that those forms are within the scope of the present invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. The term “solvate” according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
In general the term “unbranched”, especially as used in connection with “aliphatic radical” and “alkyl radical” is to be understood as also meaning and being equivalent to “linear” meaning a not branched chain of C-atoms.
The term “condensed” according to the present invention means that a ring or ring-system is attached to another ring or ring-system, whereby the terms “annulated” or “annelated” are also used by those skilled in the art to designate this kind of attachment.
The term “ring system” according to the present invention refers to ring systems comprises saturated, unsaturated or aromatic carbocyclic ring systems which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted. Said ring systems may be condensed to other carbocyclic ring systems such as aryl groups, naphtyl groups, heteroaryl groups, cycloalkyl groups, etc.
“Optionally at least one heteroatom as ring member” is defined as having no heteroatom as ring member, one heteroatom as ring member or more than one heteroatom as ring member.
“Optionally at least mono-substituted” is defined as no hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc., or one hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc. or more than one hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc. (polysubstituted).
“Optionally mono- or polysubstituted” is defined as no hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc., or one hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc. or more than one hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc. (polysubstituted).
“Optionally substituted” is defined as no hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc., or one hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc. or more than one hydrogen radical in the mentioned radical being substituted by another radical, e.g. Cl, F, etc. (polysubstituted).
Cyclyl groups/radicals, as defined in the present invention, comprise any saturated, unsaturated or aromatic carbocyclic ring systems which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted. Cyclyl groups preferably comprise aryl, heteroaryl, cycloalkyl, heterocyclyl and/or spiro ring systems.
Heterocyclyl groups/radicals, as defined in the present invention, comprise any saturated, unsaturated or aromatic carbocyclic ring systems which are optionally at least mono-substituted and which contain at least one heteroatom as ring member. Preferred heteroatoms for these heterocyclyl groups are N, S or O.
Aliphatic radicals/groups, as referred to in the present invention, are optionally mono- or polysubstituted and may be branched or unbranched, saturated or unsaturated. Unsaturated aliphatic groups, as defined in the present invention, include alkenyl and alkinyl radicals. Saturated aliphatic groups, as defined in the present invention, include alkyl radicals Preferred aliphatic radicals according to the present invention include but are not restricted to methyl, ethyl, vinyl (ethenyl), ethinyl, propyl, n-propyl, isopropyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, n-butyl, iso-butyl, sec-butyl, tert-butyl butenyl, butinyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Preferred substituents for aliphatic radicals, according to the present invention, are a C1-4 alkyl group, a linear or branched C1-4 alkoxy group, F, Cl, I, Br, CF3, CH2F, CHF2, CN, OH, SH, NH2, oxo, (C═O)R′, SR′, SOR′, SO2R′, NHR′, NR′R″ whereby R′ and optionally R″ for each substitutent independently represents a linear or branched C1-6alkyl group.
Alkyl radicals, as referred to in the present invention, are saturated aliphatic radicals. They may be linear or branched and are optionally substituted.
In these radicals, C1-2-alkyl represents C1- or C2-alkyl, C1-3-alkyl represents C1-, C2- or C3-alkyl, C1-4-alkyl represents C1-, C2-, C3- or C4-alkyl, C1-5-alkyl represents C1-, C2-, C3-, C4-, or C5-alkyl, C1-6-alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl, C1-7-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, C1-8-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl, C1-10-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and C1-18-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. The alkyl radicals are preferably methyl, ethyl, propyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, if substituted also CHF2, CF3 or CH2OH etc.
The term (CH2)3-6 is to be understood as meaning —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—CH2— and —CH2—CH2—CH2—CH2—CH2—CH2—; (CH2)1-4 is to be understood as meaning —CH2—, —CH2—CH2—, —CH2—CH2—CH2— and —CH2—CH2—CH2—CH2—; (CH2)4-5 is to be understood as meaning —CH2—CH2—CH2—CH2— and —CH2—CH2—CH2—CH2—CH2—, etc.
Cycloalkyl radicals, as referred to in the present invention, are understood as meaning saturated and unsaturated (but not aromatic), cyclic hydrocarbons, which can optionally be unsubstituted, mono- or polysubstituted. In these radicals, for example C3-4-cycloalkyl represents C3- or C4-cycloalkyl, C3-5-cycloalkyl represents C3-, C4- or C5-cycloalkyl, etc. With respect to cycloalkyl, the term also includes saturated cycloalkyls in which optionally at least one carbon atom may be replaced by a heteroatom, preferably S, N, P or O. However, mono- or polyunsaturated, preferably monounsaturated, cycloalkyls without a heteroatom in the ring also in particular fall under the term cycloalkyl as long as the cycloalkyl is not an aromatic system. Furthermore, C3-4-cycloalkyl represents C3- or C4-cycloalkyl, C3-5-cycloalkyl represents C3-, C4- or C5-cycloalkyl, C3-6-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl, C3-7-cycloalkyl represents C3-, C4, C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl represents C4- or C5-cycloalkyl, C4-8-cycloalkyl represents C4-, C5- or C6-cycloalkyl, C4-7-cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl represents C5- or C6-cycloalkyl and C5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl.
Examples for cycloalkyl radicals preferably include but are not restricted to cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, acetyl, tert-butyl, adamantyl, pyrroline, pyrrolidine, pyrrolidineone, pyrazoline, pyrazolinone, oxopyrazolinone, aziridine, acetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydrofurane, dioxane, dioxolane, oxathiolane, oxazolidine, thiirane, thietane, thiolane, thiane, thiazolidine, piperidine, piperazine or morpholine.
Cycloalkyl radicals, as defined in the present invention, are optionally mono- or polysubstituted by substitutents independently selected from a C1-4 alkyl group, a linear or branched C1-6 alkoxy group, F, Cl, I, Br, CF3, CH2F, CHF2, CN, OH, SH, NH2, oxo, (C═O)R′, SR′, SOR′, SO2R′, NHR′, NR′R″ whereby R′ and optionally R″ for each substitutent independently represents a linear or branched C1-6-alkyl group.
An aryl radical, as referred to in the present invention, is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. These aryl radicals may optionally be mono- or polysubstituted by substitutents independently selected from a C1-4 alkyl group, a linear or branched C1-6 alkoxy group, an optionally at least mono-substituted phenyl group, F, Cl, I, Br, CF3, CH2F, CHF2, CN, OH, SH, NH2, oxo, (C═O)R′, SR′, SOR′, SO2R′, N(C═O)—OR′, NHR′, NR′R″ whereby R′ and optionally R″ for each substitutent independently represents a linear or branched C1-6-alkyl group. Preferred examples of aryl radicals include but are not restricted to phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl or anthracenyl radicals, which may optionally be mono- or polysubstituted, if not defined otherwise.
An alkyl-aryl radical, as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain which is bonded to an aryl group, as defined above. A preferred alkyl-aryl radical is a benzyl group, wherein the alkyl chain is optionally branched or substituted. Preferred substituents for alkyl-aryl radicals, according to the present invention, are F, Cl, Br, I, NH2, SH, OH, SO2, CF3, carboxy, amido, cyano, carbamyl, nitro, phenyl, benzyl, —SO2NH2, C1-6 alkyl and/or C1-6-alkoxy.
A heteroaryl radical is understood as meaning heterocyclic ring systems which have at least one aromatic ring and may optionally contain one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur and may optionally be mono- or polysubstituted by substitutents independently selected from a C1-4 alkyl group, a linear or branched C1-6 alkoxy group, F, Cl, I, Br, CF3, CH2F, CHF2, CN, OH, SH, NH2, oxo, (C═O)R′, SR′, SOR′, SO2R′, NHR′, NR′R″ whereby R′ and optionally R″ for each substitutent independently represents a linear or branched C1-6-alkyl group. Preferred examples of heteroaryls include but are not restricted to furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole and quinazoline.
An alkyl-heteroaryl (or alkyl-heterocyclyl) radical, as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain which is bonded to an heteroaryl (heterocyclyl) group, as defined above.
With respect to compounds of general formula (I) of the present invention, Y and Z may form an unsaturated (Y═Z) or a saturated (Y—Z) bond which is illustrated below.

A preferred embodiment of the present invention are compounds of general formula (Ia)
                in which        Y represents CH and Z represents C—R6; C—CHR7R7a; a C—(C═O)—R8 group; a C—CH2(SO2)—R9 group; a C—CH2(SO2)—NR10R10a group; or a C—(C═O)—NR10R10a group;        and        R1, R6, R7, R7a, R8, R9, R10, R10a and R19 are defined as above.        
Another preferred embodiment of the present invention are compounds of general formula (Ib),
                in which        Y represents CH2; C—R11R12; a CH—(C═O)—R16 group; a CH—(SO2)—R17 group; CH—(SO2)—NR18R18a group; or a CH—(C═O)—NR18R18a group and Z represents CH—R6; CH—CHR7R7a; a CH—(C═O)—R8 group; a CH—CH2(SO2)—R9 group; a CH—CH2(SO2)—NR10R10a group; or a CH—(C═O)—NR10R10a group;        and        R1, R6, R7, R7a, R8, R9, R10, R10a, R11, R12, R16, R17, R18, R18a and R19, are defined as above.        
A preferred embodiment of the present invention are compounds of general formula (Ia), wherein                Z represents C—R6, thus leading to the compounds being of a structure according to general formula (Iaa)        
                with R1, R6 and R19 being defined as above.        
Another preferred embodiment of the present invention are compounds of general formula (I), (Ia), (Ib) and (Iaa) wherein                R6 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing heterocyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system;        preferably R6 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system;        more preferably R6 represents a hydrogen atom; a linear or branched, saturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group;        most preferably R6 represents a linear or branched, saturated, optionally at least mono-substituted C1-6-alkyl group; an optionally at least mono-substituted phenyl group.        
Another preferred embodiment of the present invention are compounds of general formula (I), (Ia), (Ib) or (Iaa) wherein                R1 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing heterocyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system;        preferably R1 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; an branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system;        more preferably R1 represents a hydrogen atom; a linear or branched, saturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group; an optionally at least mono-substituted alkyl-aryl group; an optionally at least mono-substituted alkyl-heterocyclyl group;        most preferably R1 represents a linear or branched, saturated, optionally at least mono-substituted C1-4-alkyl group; an optionally at least mono-substituted phenyl group; an optionally at least mono-substituted benzyl group; an optionally at least mono-substituted CH2-heterocyclyl group.        
Another preferred embodiment of the present invention are compounds of general formula (I), (Ia), (Ib) and (Iaa) wherein                R19 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing heterocyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system;        preferably R19 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system;        more preferably R19 represents a hydrogen atom; a linear or branched, saturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; an optionally at least mono-substituted aryl group;        most preferably R19 represents a linear or branched, saturated, optionally at least mono-substituted C1-4-alkyl group; an optionally at least mono-substituted phenyl group.        
A highly preferred embodiment of the present invention are compounds of general formula (Iaa)
                wherein        R6 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing heterocyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system;        preferably R6 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system;        more preferably R6 represents a hydrogen atom; a linear or branched, saturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group;        most preferably R6 represents a linear or branched, saturated, optionally at least mono-substituted C1-6-alkyl group; an optionally at least mono-substituted phenyl group.and/or        R1 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing heterocyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system;        preferably R1 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; an branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system;        more preferably R1 represents a hydrogen atom; a linear or branched, saturated, optionally at least mono-substituted aliphatic group; an optionally at least mono-substituted aryl group; an optionally at least mono-substituted alkyl-aryl group; an optionally at least mono-substituted alkyl-heterocyclyl group;        most preferably R1 represents a linear or branched, saturated, optionally at least mono-substituted C1-6-alkyl group; an optionally at least mono-substituted phenyl group; an optionally at least mono-substituted benzyl group; an optionally at least mono-substituted CH2-heterocyclyl group;and/or        R19 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-aryl group in which the aryl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing heterocyclyl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; or a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted alkyl-heterocyclyl group in which the heterocyclyl group may be condensed with another, optionally at least mono-substituted mono- or polycyclic ring system;        preferably R19 represents a hydrogen atom; a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; an optionally at least mono-substituted aryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system;        more preferably R19 represents a hydrogen atom; a linear or branched, saturated, optionally at least mono-substituted aliphatic group; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted alkoxy radical; an optionally at least mono-substituted aryl group;        most preferably R19 represents a linear or branched, saturated, optionally at least mono-substituted C1-4-alkyl group; an optionally at least mono-substituted phenyl group;optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.        
Most highly preferred are compounds of general formula (I) as described above, selected from the group consisting of:    (2S)-ethyl 2-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)propanoate;    (2S)-ethyl 2-((3aR,6aS)-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)propanoate;    (2S)-ethyl 2-((3aS,6aR)-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)propanoate;    (2S)-ethyl 2-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)propanoate;    (2S)-ethyl 2-((3aR,6aS)-5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)propanoate;    (2S)-ethyl 2-((3aS,6aR)-5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)propanoate;    (2S)-ethyl 2-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methylbutanoate;    (2S)-ethyl 2-(3aR,6aS)-4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methylbutanoate;    (2S)-ethyl 2-((3aS,6aR)-4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methylbutanoate;    (2S)-ethyl 2-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methylbutanoate;    (2S)-ethyl 2-(3aR,6aS)-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methylbutanoate;    (2S)-ethyl 2-(3aS,6aR)-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methylbutanoate;    (2S)-methyl 4-methyl-2-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)pentanoate;    (2S)-methyl 4-methyl-2-((3aR,6aS)-4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)pentanoate;    (2S)-methyl 4-methyl-2-((3aS,6aR)-4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)pentanoate;    (2S)-methyl 2-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methylpentanoate;    (2S)-methyl 2-((3aR,6aS)-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methylpentanoate;    (2S)-methyl 2-((3aS,6aR)-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methylpentanoate;    (2S)-methyl 2(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H) yl)-3-phenylpropanoate;    (2S)-methyl 2-((3aR,6aS)-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydro cyclopenta[c]pyrrol-2(1H)-yl)-3-phenylpropanoate;    (2S)-methyl 2-((3aS,6aR)-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-phenylpropanoate;    (2S)-methyl 2-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-phenylpropanoate;    (2S)-methyl 2-((3aR,6aS)-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-phenylpropanoate;    (2S)-methyl 2-((3aS,6aR)-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-phenylpropanoate;    (2S)-methyl 2-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-phenylacetate;    (2S)-methyl 2-((3aR,6aS)-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-phenylacetate;    (2S)-methyl 2-((3aS,6aR)-(4-oxo-5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-phenylacetate;    (2S)-methyl 2-(5-butyl-4-oxo-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-phenylacetate;    (2S)-methyl 2-(3aR,6aS)-(5-butyl-4-oxo-1,3a,4,6a-tetrahydro cyclopenta[c]pyrrol-2(1H)-yl)-2-phenylacetate;    (2S)-methyl 2-((3aS,6aR)-5-butyl-4-oxo-1,3a,4,6a-tetrahydro cyclopenta[c]pyrrol-2(1H)-yl)-2-phenylacetate;    (2S)-methyl 3-1H-indol-3-yl)-2-(3a,6a-cis)-6-oxo-5-phenyl-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)propanoate; or    (2S)-methyl 2-((3a,6a-cis)-5-butyl-6-oxo-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl-3-(1H-indol-3-yl)propanoate;            optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.        
Another aspect of the present invention refers to a process for obtaining substituted bicyclic tetrahydropyrrole compounds of general formula (Ia), characterized in that at least one substituted pyrroline compound of general formula (II),
wherein R1 has the meaning given above, is reacted in presence of a catalyst such as e.g. CO2(CO)8, an apolar dissolvent such as e.g. DCE (dichloroethane) and an additive (Lewis base) such as e.g. DMSO, thioanisole, cyclohexylamine, preferably DMSO at a reflux temperature between 20 and 100° C., preferably between 50 and 90° C., most preferably between 80 and 90° C., with a compound of general formula (III),
wherein Z represents a CH—R6 group; a CH—CHR7R7a group; a CH—(C═O)—R8 group; a CH—CH2(SO2)—R9 group; a CH—CH2(SO2)—NR10R10a group; or a CH—(C═O)—NR10R10a group, to give compounds of general formula (Ia),
wherein the bond between Y and Z is unsaturated (Y═Z) in which Y represents a CH group and Z has the meaning as defined above.
A general scheme for compounds of general formula (Ia) with Y and Z forming an unsaturated bond (Y═Z) is given below in scheme (I):

The synthesis of 1-substituted-3-pyrrolines of general formula (II) is performed by treatment of amino acid (ethyl or methyl)esters of general formula (AA) with (Z)-1,4-dichloro-2-butene in an apolar dissolvent such as e.g. dichloromethane (DCM) at a temperature between 10° and 30° Celsius, preferably at room temperature. A reaction time which worked very well for both steps of the reaction shown above was between 20 and 30 h, especially 24 h. Another condition which turned out to be preferable was the use of an excess (e.g. 3.5 eq.) of the amino acid ester (according to formula AA) preferably in the absence of any added base. Advantageously the unreacted starting material can be easily recovered and recycled, and this direct procedure takes place without the need of nitrogen basicity deactivation by strong Lewis acids. This would be preferable when racemization-prone substrates are involved in the reaction.
Compounds of general formula (I) with Y and Z forming a saturated (Y—Z) bond are obtained by performing a 1,4-addition reaction with a compound of general formula (Ia),
